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THE BIG ISSUES

#1. THE GREATEST RISK FOR RECURRENCE OF BREAST CANCER—THE DEVELOPMENT OF SPREAD OF CANCER THROUGHOUT THE BODY—OCCURS IN THE FIRST TWO-THREE YEARS AFTER DIAGNOSIS OF APPARENTLY LOCALIZED-TO-THE-BREAST AND REGIONAL-LYMPH NODE BREAST CANCERS (STAGE I AND II CANCERS). WHY IS THIS? IF WE COULD UNDERSTAND THIS SITUATION BETTER, THEN WE COULD PERHAPS BE MUCH MORE EFFECTIVE IN OUR CHOICES OF FIRST TREATMENTS AT THE TIME OF USUAL DIAGNOSIS.

#2. IMPROVING AND TAILORING HORMONAL THERAPIES. WE HAVE HORMONAL TREATMENTS WHICH ARE EFFECTIVE FOR SOME, BUT NOT ALL WOMEN AND TUMORS, AND FOR LIMITED PERIODS ONLY.

This research is generously supported by a grant from the Breast Cancer Research Foundation, New York, NY.

Among women in low income countries when breast cancers develop, for a variety of reasons they are not treated promptly, specifically they are not surgically removed, but grow larger in the breast. In such circumstances it is common to see women with very large (6 inches or more across) tumors, but interestingly little obvious evidence of spread of these cancers to other parts of their bodies. If these patients are treated with surgery to remove these large tumors, often clinical evidence of obvious metastases very soon follows. Here is an example from a patient from Bangladesh:

Norton and Massague have suggested that such situations (big local tumor-- no evidence of distant spread) occur because tumors “self-seed” Their idea is depicted in the figure from their paper in Nature Medicine 12:875-878, 2006.

The critical activities are those indicated by the (B) green arrows and (E) yellow arrows where respectively tumor cells leave B a primary (in the breast) tumor (pathway B green) and come back to this tumor after circulating in the bloodstream or leave E a metastatic tumor (in some distant tissue like the liung or liver) (pathway E yellow) and come back to this tumor after circulating in the bloodstream.

Norton and Massague suggest that tumor cells taking these different pathways will have different characteristics—different gene profiles.

In this research we will obtain multiple small hollow needle tissue samples from different parts of such large tumors from 100 Bangladeshi women and Dr Jim Hicks in the Norton/Massague group will study them to see if indeed, as Norton and Massague predict, there is evidence of different gene profiles. As of September 2012, we have collected sets of an average of 4 core biopsies from over 100 patients and are distributing these to laboratory investigators.

Why is this research important?

Finding different gene profiles in cells of the same tumor allows then determining what these specific genes do and getting a better understanding of how tumors behave. Such understanding is a prelude to better controlling these, indeed all, breast cancers and preventing the high rates of recurrence in the first two-three years after surgical removal.

WHAT WE ALREADY KNOW

Hormonal therapies appear indicated for about two thirds of women with breast cancers—their tumors are found to be hormone sensitive—to have expression of estrogen and or progesterone hormonal receptors. But hormonal therapies are imperfect—they work very well for some women and not others, and they have significant bad side effects in some women.

Through several projects, IBCRF researchers are studying how we can make one very good hormonal therapy—tamoxifen--safer and more effective:

Biology Study 2: A Prospective pharmacogenomic study of tamoxifen

Tamoxifen does not work to control breast cancer growth in all women. One explanation may be that there are genetic differences among women. If we can identify these genetic differences, we can better select who should get tamoxifen treatment.

Recent data suggest that genetic differences in tamoxifen metabolizing enzymes, most importantly cytochrome P450 CYP2D6, which controls the plasma concentrations of the strong anti-breast cancer growth metabolite Endoxifen, account for significant levels of variability in responses to this medicine.

With collaborators at Indiana University, in 97 Vietnamese women 39 (40.2%) had CYP2D6/*10*10 and 44 (45.4%) had CYP2D6/*10*1 (both intermediate metabolizer) status, while in 146 Filipino women, these frequencies were 29.4% and 50.7% respectively. In these Vietnamese and Filipino women, plasma Endoxifen concentrations were significantly associated with CYP2D6 genotypes.

The overall goal of the present study is to investigate in 740 Filipino and Vietnamese women with breast cancer all receiving tamoxifen adjuvant therapy in a clinical trial, the association of Endoxifen concentrations and survival without evidence of disease.

A Phase III IBCRF Study generously funded through grants from the Breast Cancer Research Foundation (BCRF), New York

WHAT WE ALREADY KNOW

For women with breast cancers that are hormone sensitive (that is that have hormonal receptors) there are treatment options including: chemotherapy, tamoxifen, ovary removal or ovarian function-suppression with medicines. It has become clear that over the long term the therapies directed specifically at the hormonal receptors are of the greatest importance in preventing disease recurrence.

However using the current best hormone sensitivity markers, no treatments are perfect, and so the challenge is how to improve the specific treatment selected for individual women. Currently we just give treatments we hope are best and wait to see if indeed over time things go well and there is no recurrence of the cancer.

In order to improve upon breast cancer outcomes associated with the surgical removal of ovaries, a treatment approach IBCRF has been studying carefully and championing, it is critically important to better understand the effects of oophorectomy on the primary breast tumors of individual women.

This is particularly important with respect to the effects of ovarian removalon the primary tumour at different times of the menstrual cycle which we are currently studying. (insert LINK) In Vietman, modified radical mastectomy plus oophorectomy and Tamoxifen is a standard of care for premenopausal women with operable hormone sensitive (“Estrogen receptor positive”) breast cancer.

Given that two operations are be performed with this treatment (i.e. mastectomy and surgical oophorectomy), if the surgical oophorectomy is performed before the mastectomy, this provides a unique opportunity to explore the early effects of surgical oophorectomy on the breast tumors. Such exploration can yield new information which can allow for better tailoring of these hormonal and other treatments for Filipina patients.

Study Plan:

76 premenopausal women with stage II-IIIb ER positive breast cancer whose treatment will include mastectomy, surgical oophorectomy plus tamoxifen will be recruited from the Breast Surgery Department at Hospital K Hanoi, Vietnam. Each participant will have the same treatment: surgical oophorectomy followed by mastectomy one month later. Tamoxifen will then be given. In this study blood samples and breast tumour tissue will be taken before any surgeries, then two weeks and four weeks after the ooophorectomy surgery and studied for changes in levels of estradiol, Ki67 (a marker of proliferation in the tumors) and levels of hormonal receptors. We will also follow women for 5 years to investigate a possible relationship between these markers and recurrence of breast cancer. This study will open early in 2011.

A brief report of the interesting initial results of this research has been prepared and submitted to a scientific journal for publication. When these results are published they will also be presented on this website.

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